This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nbs1 and Mre11 are linked to the Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively, and the affected patients are predisposed to cancer. Mre11, Nbs1 and Rad50 form a conserved protein complex that is required for the maintenance of genome stability. Recent studies have also uncovered new roles of MRN in S-phase related events, such as replication control, replication checkpoint and prevention of DSB formation in S-phase, but detailed mechanisms are not clear. We propose to investigate the mechanisms underlying the critical roles of the Mre11/Rad50/Nbs1 complex (MRN) in preserving genome integrity, especially in mediating S-phase-associated DNA damage responses.